The goal of Research Project by Veazey (Nonhuman primate studies to develop an RNAi microbicide) is to evaluate the efficacy, safety, potency, and duration of effect of RNA interference (RNAi) technology in preventing vaginal transmission of HIV-1, using the simian/human immunodeficiency virus (SHIV) vaginal transmission model in rhesus macaques. The Leader will be Ronald Veazey, DVM, PhD, and the project will be located at the Tulane National Primate Research Center, Tulane, LA. For these studies, we will receive CCR5 specific RNAi from the Research Support Core which we will use in determining the depth or penetration, level of CCR5 downregulation, safety, and efficacy in preventing vaginal transmission of the CCR5 tropic SHIV162P3 virus to macaques when used as a microbicide. This project will coordinate closely with the leaders of the other research projects involved in testing these drugs in human explant and murine model systems (Research Projects by Lieberman and Palliser, and Research Support Cores). We will examine the safety and efficacy of the RNAi after topical application to the macaque vagina, by performing colposcopy and vaginal biopsy after vaginal administrations of the drugs to carefully rule out local inflammatory responses and to monitor levels of CCR5 expression in various tissues. CCR5 specific RNAi will also be assessed for its efficacy in downregulating CCR5 expression in vaginal and other tissues, as well as its efficacy and duration of effects in preventing vaginal SHIV transmission to macaques. The specific aims of research project by Veazey are to: Specific Aim 1. Determine whether siRNAs are efficiently taken up by vaginal and cervical tissues in the macaque and whether vaginal application of siRNAs silences macaque CCR5 expression in vivo; Specific Aim 2. Determine whether first generation, unmodified CCR5 siRNAs given before and after challenge with SHIV 162P3 protect against vaginal transmission; Specific Aim 3. Evaluate dose response to determine the amount of unmodified siRNA required to protect against challenge, and whether increasing amounts of siRNA cause vaginal irritation, inflammation, interferon induction or other unanticipated toxicity, and; Specific Aim 4. Determine whether optimized siRNAs against CCR5 and viral sequences alone and in combination provide superior protection than unmodified CCR5 siRNAs alone.